Drug Resistance Increasing in Children

Indeed, drug resistance is emerging in children on ART in South Africa.

One study described a large number of resistance mutations found in thirteen children at Kalafong Hospital in Pretoria, who were started on a protease inhibitor-based regimen when they were younger than 36 months of age (mean age 22.4 months), some of whom had already been switched to a second line NNRTI regimen. The mean duration of treatment at testing was 45.9 months. 'All these children were deemed to be at high risk as they suffered co-morbid conditions and had documented poor adherence,' according to the posters authors. Three of the children had WHO Stage 3 disease, and ten had WHO stage 4 disease; while 62% of their caregivers reported poor adherence, and 54% had a history of missed clinic appointments. Only one had ever achieved an undetectable viral load.

Resistance testing found that all of these children had virus resistant to nucleoside analogues (the 3TC-related M184V mutation being the most common), five had major protease inhibitor resistance mutations, and nine had resistance to mutations to non-nucleoside analogue reverse transcriptase inhibitors (NNRTI, i.e. efavirenz or nevirapine) only one of these had been exposed to nevirapine as PPTCT.

A second poster presentation found drug resistance was more common in paediatric than adult patients experiencing virological failure on their second line protease inhibitor-based regimen at Tshwane Academic Hospital (Pretoria).8 All patients had been started on d4T/3TC with either nevirapine or efavirenz, and they were all switched to either AZT/ddI/ or a variation (AZT/abacavir) with ritonavir-boosted lopinavir (Kaletra / Aluvia).

About half of the failing adult patients showed no evidence of resistance at all, suggesting that they simply were not taking their treatment, but the virus from 91% of the children (30 out of 33) of the paediatric patients failing treatment had resistance mutations. In these children, virus in seven out of 33 (21%) had major PI mutations, five had more than three PI mutations, and 27.3% still showed evidence of the K103 mutation conferring resistance to NNRTIs (note, the mutation would probably have been detected in more children if they were still taking nevirapine or efavirenz). Finally, 75.8% of the children had virus that was resistant to 3TC, and 18.2 % had multiple thymidine analogue mutations (TAMs) that significantly decrease the chances of responding to subsequent nucleoside analogues.

Notably, some of these children had only moderate levels of viral load which in the presence of less than universal resistance to the PIs, suggested that they may have been taking their treatment, but that adherence was suboptimal.

Nevertheless, the authors concluded that children exhibited increased levels of resistance to all three drug classes, perhaps because of higher levels of viral replication that typically occur in children or perhaps because some of them had previous exposure to unboosted PI therapy (ritonavir monotherapy).

Dr Theresa Rossouw of the University of Pretoria, who was the lead author of the latter poster, also gave an oral presentation describing findings from the Southern African Treatment and Resistance Network (SATuRN), which is monitoring emerging patterns of drug resistance in the region.9 She described higher rates of resistance among 49 children in SATuRN (though it is not clear to what extent these patients overlap) with PI resistance being documented in almost one third of the patients and three or more PI resistance mutations in 20.4%. NNRTI Resistance was seen in 21/49 (42.86%). Resistance to the nucleoside analogues was detected in 41/49 (83.67%), with eleven out of 49 (22.45%) with TAMS, and eight out of 49 (16.28%) with three or more TAMs. She noted several other South African cohorts have also documented high levels of resistance among children failing treatment.

Resistance, and limited treatment options will make it more difficult for these children to live with HIV into adolescence, when other challenges to treatment success seem to emerge.